In recent years it has become quite evident that certain natural oligonucleotides exhibit growth regulatory function. Various oligonucleotides appear to regulate RNA polymerases and initiate cellular differentiation. Such an oligonucleotide pppA2'p5'A2'p5'A has recently been discovered in interferon treated cells and appears to be responsible for inhibition of cellular proliferation by regulating cellular messenger RNA synthesis. This trimer is active at subnanomolar levels and is not degraded by the usual ribonucleases due to the 2',5'-phosphodiester linkage. The aim of the present proposal is to synthesize such oligonucleotides, especially those containing a 2',5'-phosphodiester linkage and make such oligonucleotides available for antitumor evaluation in cell culture and in animal tumor model systems. It has been shown that certain oligonucleotides can enter tumor cells and it is hoped that such oligonucleotides will exert regulatory action which will control abnormal cellular proliferation characteristic of the cancer cell. Several different types of dinucleoside-2',5'-phosphate derivatives will be prepared and studied as inhibitors of DNA and RNA polymerase. Some monomeric derivatives such as tubercidin, toyocamycin and sangivamycin which exhibit definite antitumor activity in animal systems will also be studied as the 2',5'-linked oligomers with the hope that greater specificity of antitumor action might be obtained. Studies will be made of the synthesis and structure of certain oligonucleotide units structurally related to polyadenosine-diphosphate ribose (ADPR) which has been shown in eucaryotic cells to be obligatory for cell growth and division. The structure of poly ADPR has recently been shown to be that of an 2',1-alpha-D-O-ribofuranosyl-5-phosphate polymeric linkage (V). A synthesis of the monomer (1" yields 2') alpha-D-ribofuranosyladenosine-5',5"bis phosphate (V) and related analog derivatives is proposed. These oligonucleotides will be evaluated initially in an L-1210 cell culture system. Active oligonucleotides will then be synthesized in quantity sufficient for in vivo testing.